Children of the 1970/80s can easily recall that famous “How many licks does it take to get to the center of a Tootsie Pop?” commercial. Well, there’s a Hatch-Waxman version of that question: “How many approvals does it take to get to the center of 3-year exclusivity?” While the world has known for a couple of years the answer to the Tootsie Pop question, FDA only recently provided an answer to the Hatch-Waxman version of the question. And as with other recent 3-year exclusivity issues, the answer has come up in the context of abuse-deterrent opioids (see our previous posts here, here, here, and here). But before we give up the answer, some background is on order. . . .

XTAMPZA ER was approved just days after the expiration of a period of 3-year exclusivity applicable to OXYCONTIN. That exclusivity was granted based on FDA’s April 16, 2013 approval of NDA 022272/S014, and was coded in the Orange Book as “M-153” (which is defined as: “ADDITION OF INFORMATION REGARDING THE INTRANASAL ABUSE POTENTIAL OF OXYCONTIN”). In a March 3, 2015 Memorandum, the CDER Exclusivity Board explained the Agency’s decision to grant a period of 3-year exclusivity with respect to the April 16, 2013 approval of NDA 022272/S014 (see our previous post here), as well as the scope of that exclusivity: “the scope of 3-year exclusivity in this instance is limited to the addition of information to the [OXYCONTIN] labeling regarding the reduction of abuse via the intranasal route.”

In support of it’s NDA for XTAMPZA ER, Collegium conducted a couple of its own clinical investigations: an efficacy trial and a human abuse liability study assessing deterrence of intranasal abuse (Study CP-OXYDET-21). FDA subsequently granted Collegium a period of 3-year exclusivity for XTAMPZA ER that expires on April 26, 2019 and that is coded in the Orange Book as “NP” (for “New Product” exclusivity).

In light of a then-pending NDA for Inspirion Delivery Sciences, LLC’s (“Inspirion’s”) ROXYBOND (oxycodone HCl) Tablets, 5 mg, 15 mg, and 30 mg (NDA 209777) for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate, the CDER Exclusivity Board once again earlier this year had to assess the scope of 3-year exclusivity – in this case for XTAMPZA ER – and whether that exclusivity served as an obstacle to the approval of ROXYBOND. In a 20-page Memorandum dated April 20, 2017, the CDER Exclusivity Board concluded that “Xtampza ER’s exclusivity based on study CP-OXYDET-21 covers the specific formulation of Xtampza ER associated with its inlranasal [abuse-deterrrent] properties,” and that “[b]ecause RoxyBond’s formulation associated with its intranasal AD properties is different from that of Xtampza ER, it does not share any exclusivity-protected conditions of approval of Xtampza ER” and the 3-year NP exclusivity applicable to XTAMPZA ER “should not block approval of RoxyBond” (emphasis added). So, FDA approved NDA 209777 for ROXYBOND on April 20, 2017. (By the by, Pharmaceutical Manufacturing Research Services, Inc. recently filed a Complaint in the U.S. District Court for the Eastern District of Pennsylvania challenging FDA’s ROXYBOND approval.)

That’s right! Although FDA previously articulated what we’ve dubbed a “route of abuse” approach to abuse-deterrent opioid 3-year exclusivity, that approach has evolved. It’s been modified a bit to account for formulation differences and the type of abuse-deterrence technology used (e.g., physical/chemical barriers, agonist/antagonist combinations, aversion, delivery system, and others discussed in FDA guidance). FDA explains the general exclusivity framework as follows:

[I]n assessing the scope of 3-year exclusivity for a single-entity drug product containing the same active moiety as a previously approved single-entity drug product, the Agency looks at the innovative change(s) represented by the later-approved drug product relative to the previously approved drug product. Exclusivity for the later-approved drug product cannot cover any condition of approval for which “new clinical investigations” were not “essential.” If an earlier-approved drug product was approved for a particular condition of approval, new clinical investigations would not be considered “essential” to support the same condition of approval for a later-approved drug product containing the same active moiety. Rather, the new clinical investigations would be considered essential only to support a condition of approval for the later-approved drug product that is different from the condition of approval of the earlier-approved drug product. Because 3-year exclusivity generally covers only the differences from a previously approved product, as a practical matter a later-approved product is likely to have a narrower scope of exclusivity than the product approved previously.

The following example provided by FDA illustrates the above concepts:

The scope of exclusivity based on new clinical investigations that establish for the first time that an active moiety previously approved only as a single-entity, IR drug product can be formulated as a safe and effective extended-release drug product could potentially block approval of subsequent 505(b)(2) NDA for a single-entity, extended-release drug product containing that active moiety.

Any determination of the scope of exclusivity for a subsequent 505(b)(2) NDA for an extended-release drug product containing the same active moiety would generally follow the framework described above in which the innovative change(s) represented by this product would be assessed relative to the first approved extended-release product. If, for instance, the subsequent product uses different extended-release technology for which new clinical investigations were essential, the scope of exclusivity for this subsequent product would only cover this innovative change.

FDA’s evolution in thinking has caused the Agency to reassess the scope of previously granted exclusivity. According to FDA:

In light of the evolution of the Agency’s approach to assessing 3-year exclusivity for certain [abuse-deterrent] opioids . . . . [the CDER Exclusivity Board] reassessed the scope of OxyContin’s 3-year exclusivity related to S-14. Applying an approach to the scope of 3-year exclusivity for [abuse-deterrent] opioids . . . in which the scope is defined by two primary characteristics: (1) the abuse route (intranasal); and (2) the type of abuse deterrence applied (physiochemical properties), the Board recommended that the scope of OxyContin exclusivity be limited to the condition of approval supported by the intranasal [human abuse liability] study, i.e., “labeling describing the expected reduction of abuse of a single-entity oxycodone by the intranasal route of administration due to physiochemical properties.”

With that reassessment, FDA then defined the narrowing scope of each period of successive 3-year exclusivity for single-entity oxycodone:

The approval of supplement S-14 for OxyContin established for the first time that a single-entity oxycodone product could be formulated with physicochemical properties expected to reduce intranasal abuse, and the resulting scope of exclusivity reflects this innovation. Xtampza ER, like OxyContin, is also a single-entity oxycodone product with physicochemical properties expected to reduce intranasal abuse. The [human abuse liability] study supporting approval of Xtampza ER with an intranasal [abuse-deterrent] claim, CP-OXYDET-21, was not essential to show that a single-entity oxycodone product could be formulated with physicochemical properties expected to reduce intranasal abuse. Approval of OxyContin S-14 had already established that. Rather, the study was essential to support that Xtampza ER’s particular formulation contributes to its intranasal [abuse-deterrent] properties. Specifically, Study CP-OXYDET-21 demonstrated that, as a result of Xtampza ER’s specific formulation, intranasal administration of crushed Xtampza ER resulted in a substantially lower response to Drug Liking, High, and Take Drug Again measures, compared to IR oxycodone. The Board thus recommends that the scope of Xtampza ER’s 3-year exclusivity based on study CP-OXYDET-21 be limited to “labeling describing the expected reduction of abuse of Xtampza ER by the intranasal route of administration due to physicochemical properties.”

Because ROXYBOND uses a combination of excipients that imparts physical and chemical barriers that make it difficult to manupulate and abuse the drug product, and that formulation differs from XTAMPZA ER to achieve its intranasal abuse-deterrent properties, FDA concluded that the approval of ROXYBOND (NDA 209777) was not blocked by XTAMPZA ER’s 3-year exclusivity.

So, how many approvals does it take to get to the center of 3-year exclusivity? Well, the answer will depend on the starting point, but apparently it’s not too many approvals in the context of abuse-deterrent opioids. Furthermore, because FDA now defines the scope of 3-year exclusivity for an abuse-deterrent drug to encompass not only the route of abuse, but also the type of abuse-deterrence technology used, we assume that there will be far fewer instances in which 3-year exclusivity could serve as a block to abuse-deterrent opioid 505(b)(2) NDA approval.